Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers

纳米级金属有机框架实现放射治疗-放射动力学治疗并提供 CpG 寡脱氧核苷酸以生成肿瘤疫苗并增强头颈癌的免疫治疗

• 批准号: 10450090
• 负责人: Wenbin Lin
• 金额: $ 49.43万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450090
• 关键词: Abscopal effect; Address; Affect; Aftercare; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; CPG-oligonucleotide; Cancer Patient; Cancer Vaccines; Cations; Cells; Chemistry; Clinical; Combination immunotherapy; Coupled; Data; Dendritic cell activation; Disease; Disseminated Malignant Neoplasm; Dose; Extracellular Matrix; Fibroblasts; Genes; Goals; Hafnium; Head; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Hydroxyl Radical; Immune; Immune checkpoint inhibitor; Immune system; Immunologic Adjuvants; Immunologic Memory; Immunologics; Immunotherapy; Infiltration; Interferon Type I; Interferon Type II; Interferons; Irradiated tumor; Localized Malignant Neoplasm; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Mediating; Metals; Methods; Mission; Modeling; Molecular; Mouth Neoplasms; Mus; PD-1 blockade; PD-1/PD-L1; PD-L1 blockade; Pathway interactions; Patients; Porphyrins; Process; Proteins; Public Health; RNA; Radiation; Radiation Dose Unit; Radiation therapy; Radiation-Sensitizing Agents; Recurrence; Recurrent Malignant Neoplasm; Research; Resistance; Roentgen Rays; S-Phase Fraction; Signal Transduction; Singlet Oxygen; Squamous cell carcinoma; Stimulator of Interferon Genes; Surface; T cell response; T-Cell Activation; T-Cell Proliferation; Testing; Time; Toxic effect; Treatment outcome; Tumor-infiltrating immune cells; United States National Institutes of Health; adaptive immune response; anti-cancer; antitumor effect; checkpoint therapy; chemotherapy; clinically relevant; effective therapy; effector T cell; genetic signature; immune activation; immune checkpoint blockade; improved; innate immune mechanisms; innovation; irradiation; macrophage; nanomedicine; nanoscale; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; palliative; particle; programmed cell death protein 1; radioresistant; response; systemic toxicity; tumor; tumor microenvironment; tumor-immune system interactions; x-ray irradiation

Checkpoint blockade antibodies targeting PD-1 have demonstrated improved survival in metastatic head and neck squamous cell carcinomas (HNSCC) patients by reactivating effector T cells that have infiltrated the tumor microenvironment. However, PD-1 blockade still has low overall response rates approximating 18%, suggesting that the different treatment outcomes are due to intrinsic differences in the patients' diseases, such as tumor microenvironments. Recently, we have developed a new class of radioenhancers, nanoscale metal- organic frameworks (nMOFs), that can alter the immune microenvironment. Constructed via coordination between hafnium-oxo clusters and porphyrin-like molecules, nMOFs generate both hydroxyl radicals and singlet oxygen in a process termed radiotherapy-radiodynamic therapy (RT-RDT). The objective in this application is to define the mechanisms by which RT-RDT and nMOF-enabled immunotherapy alter the immune microenvironment in order to sensitize HNSCCs to checkpoint blockade. Our central hypothesis is that nMOFs can deliver the CpG oligodeoxynucleotides and synergize with RT-RDT-induced antigen release and Type I IFN expression, which stimulates CD8+ and CD4+ T cell proliferation and infiltration into HNSCCs to regress both irradiated and non-irradiated tumors treated with PD-1/PD-L1 blockade. The goal for this proposed research is to identify a novel therapy and define the mechanisms by which it alters the immune microenvironment to sensitize HNSCCs and possibly other cancers to current clinical immunotherapies. This project will use innovative molecularly tunable nMOFs having unprecedented radioenhancement via the unique RT-RDT mechanism. This proposal is significant because it addresses an unmet need of treating radioresistant and metastatic HNSCCs both directly via RT-RDT and by acting as an immunostimulant to enhance the efficacy of existing checkpoint inhibitors. This proposal will test the central hypothesis by pursuing four specific aims: (1) define the cellular mechanisms of innate immune activation after RT-RDT; (2) determine how RT- RDT affects the tumor microenvironment in squamous cell cancers; (3) evaluate the contributions of different immune components on the efficacy of RT-RDT and immunotherapy combinations; and (4) determine effective therapies for HNSCCs resistant to PD-1/PD-L1 blockade. Aim 1 will treat cells and ex vivo stimulated or cultured immune components with nMOFs and radiation to determine how RT-RDT initiates STING and Type I interferon signaling in the tumor microenvironment. Aim 2 will determine how the tumor microenvironment and extracellular matrix are affected by nMOF-mediated RT-RDT. Aim 3 will evaluate the contribution of different immune components to the anticancer efficacy of nMOFs. Aim 4 will use primary oral tumor models that are resistant to PD-1/PD-L1 blockade as a model to identify novel immunotherapy combinations that synergize with RT-RDT. Ultimately, this project will afford new therapeutic strategies using clinically relevant nanomedicines to enhance both the radiation therapy and immunological rejection of HNSCCs.

针对 PD-1 的检查点阻断抗体已证明可改善转移性头部和 通过重新激活已浸润颈部鳞状细胞癌 (HNSCC) 的效应 T 细胞 肿瘤微环境。然而，PD-1 阻断的总体缓解率仍然较低，约为 18%， 表明不同的治疗结果是由于患者疾病的内在差异造成的，例如 如肿瘤微环境。最近，我们开发了一种新型放射增强剂，纳米级金属- 有机框架（nMOF），可以改变免疫微环境。通过协调构建 在铪氧簇和类卟啉分子之间，nMOF 既产生羟基自由基， 称为放射治疗-放射动力学治疗 (RT-RDT) 的过程中的单线态氧。本次活动的目的是 该应用程序的目的是定义 RT-RDT 和 nMOF 启用的免疫疗法改变 免疫微环境，以使 HNSCC 对检查点封锁敏感。我们的中心假设是 nMOF 可以传递 CpG 寡脱氧核苷酸并与 RT-RDT 诱导的抗原释放产生协同作用 I 型 IFN 表达，刺激 CD8+ 和 CD4+ T 细胞增殖并浸润到 HNSCC 使用 PD-1/PD-L1 阻断治疗的照射和未照射肿瘤均得以消退。为此目的 拟议的研究旨在确定一种新疗法并确定其改变免疫的机制 使 HNSCC 和可能的其他癌症对当前临床免疫疗法敏感的微环境。这 该项目将使用创新的分子可调谐 nMOF，通过独特的 RT-RDT机制。该提案意义重大，因为它解决了治疗抗辐射的未满足的需求 和转移性 HNSCC 直接通过 RT-RDT 和作为免疫刺激剂来增强 现有检查点抑制剂的功效。该提案将通过追求四个具体的内容来检验中心假设 目标：（1）定义RT-RDT后先天免疫激活的细胞机制； (2) 确定RT- RDT 影响鳞状细胞癌的肿瘤微环境； (3)评估不同的贡献 免疫成分对 RT-RDT 和免疫疗法组合疗效的影响； (4) 确定有效的 对 PD-1/PD-L1 阻断耐药的 HNSCC 的治疗。目标 1 将治疗细胞并进行离体刺激或 使用 nMOF 和辐射培养免疫成分，以确定 RT-RDT 如何启动 STING 和 I 型 肿瘤微环境中的干扰素信号传导。目标 2 将确定肿瘤微环境和 细胞外基质受 nMOF 介导的 RT-RDT 影响。目标 3 将评估不同的贡献 免疫成分对 nMOF 抗癌功效的影响。目标 4 将使用原发性口腔肿瘤模型 抗 PD-1/PD-L1 阻断作为模型来识别具有协同作用的新型免疫治疗组合 与 RT-RDT。最终，该项目将利用临床相关的方法提供新的治疗策略 纳米药物可增强 HNSCC 的放射治疗和免疫排斥。